A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia

Glial cells have been proposed as a source of neural progenitors, but the mechanisms underpinning the neurogenic potential of adult glia are not known. Using single cell transcriptomic profiling, we show that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition along a linear differentiation trajectory that allows them to retain neurogenic potential while acquiring mature glial functions. Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. Molecular profiling and gene targeting of enteric glial cells in a cell culture model of enteric neurogenesis and a gut injury model demonstrate that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. Our work provides mechanistic insight into the regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits.


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ac.uk/arrayexpress/experiments/E-MTAB-5553.scATAC-seqfreshcorticaladult mouse brain (P50) data was downloaded from 10X (https://www.10xgenomics.com/resources/datasets?menu%5Bproducts.name%5D=Single%20Cell%20ATAC&page=1&configure%5Bfacets%5D%5B0%5D=chemistryVersionAndThroughput&configure%5Bfacets%5D%5B1%5D=pipeline.version&configure%5BhitsPerPage%5D=500).Adult mouse cortical scRNA-seq data from the Allen Institute for Brain Science was downloaded from https://www.dropbox.com/s/kqsy9tvsklbu7c4/allen_brain.rds.Gene lists used for cell cycle scoring were obtained from Tirosh et al., 2015.iCLIP-seqdata, which identified direct RNA targets of human CSDE1 in melanoma cells were obtained from Wurth et al., 2016.RNA-seq data on genes differentially expressed in hESCs after CSDE1 knockdown was obtained from Ju Lee et al., 2017.Human-mouse gene mappings were obtained from the NCBI HomoloGene database (ncbi.nlm.nih.gov/homologene).The GRCm38 genome is available from Ensembl.Sample size was determined based on preliminary experiments or reports in the literature.No statistical analysis was carried out prior to experiments to determine the size of experimental groups, but sample sizes were large enough to determine the effect size.Reporting for specific materials, systems and methodsWe require information from authors about some types of materials, experimental systems and methods used in many studies.Here, indicate whether each material, system or method listed is relevant to your study.If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.
Littermates (of mixed sex) were randomly assigned to experimental groups in an age range of 2-4 months.Blinding was performed wherever possible.Policy information about cell lines and Sex and Gender in ResearchCell line source(s)